Progress in our understanding of the pathogenesis of glioblastoma multiforme has been hampered by the lack of refined mouse models that fully recapitulate the genetics and biology of this disease. Genetic clues to the possible cause of glioblastoma have come from cytogenetic analysis of clinical glioma specimens that identified genetic lesions linked to oncogenic/tumor suppressor pathways, some of which include amplification or over-expression of receptor tyrosine kinases (RTKs). The experiments outlined in this proposal are designed to define the role of two RTK pathways, c-Met and PDGF, in the pathogenesis and progression of glioblastoma multiforme. Transgenic mice will be engineered to express either an activated form of c-MET or PDGF, the ligand for platelet-derived growth factor. Alterations in both of these signaling pathways are observed in clinical tumor samples and are therefore likely candidates for genes involved in gliomagenesis. This proposal will also address the importance of tumor suppressor gene loss in cooperation with RTK pathway activation to more faithfully create a mouse model of glioblastoma. This aim will be accomplished by intercrossing the RTK transgenic mice with mouse strains that do not express known tumor suppressors including Ink4a, p53, and PTEN, which are currently available in the DePinho laboratory. These models will ultimately be of great importance in determining the mechanism of glioma formation and progression as well as in creating a system in which novel therapeutic protocols can be tested. The utility of information gleaned from studies of RTKs and tumor suppressor sis not limited to glioblastoma, however, and may be relevant to many other cancers since multiple tumor types display not only tumor suppressor inactivation but also deregulated of up-regulated RTK activity.